Gatenby Robert A, Gawlinski Edward T, Gmitro Arthur F, Kaylor Brant, Gillies Robert J
Departments of Radiology, Applied Mathematics, and Optical Sciences, University of Arizona, Tucson, Arizona 85718, USA.
Cancer Res. 2006 May 15;66(10):5216-23. doi: 10.1158/0008-5472.CAN-05-4193.
The acid-mediated tumor invasion hypothesis proposes altered glucose metabolism and increased glucose uptake, observed in the vast majority of clinical cancers by fluorodeoxyglucose-positron emission tomography, are critical for development of the invasive phenotype. In this model, increased acid production due to altered glucose metabolism serves as a key intermediate by producing H(+) flow along concentration gradients into adjacent normal tissue. This chronic exposure of peritumoral normal tissue to an acidic microenvironment produces toxicity by: (a) normal cell death caused by the collapse of the transmembrane H(+) gradient inducing necrosis or apoptosis and (b) extracellular matrix degradation through the release of cathepsin B and other proteolytic enzymes. Tumor cells evolve resistance to acid-induced toxicity during carcinogenesis, allowing them to survive and proliferate in low pH microenvironments. This permits them to invade the damaged adjacent normal tissue despite the acid gradients. Here, we describe theoretical and empirical evidence for acid-mediated invasion. In silico simulations using mathematical models provide testable predictions concerning the morphology and cellular and extracellular dynamics at the tumor-host interface. In vivo experiments confirm the presence of peritumoral acid gradients as well as cellular toxicity and extracellular matrix degradation in the normal tissue exposed to the acidic microenvironment. The acid-mediated tumor invasion model provides a simple mechanism linking altered glucose metabolism with the ability of tumor cells to form invasive cancers.
酸介导的肿瘤侵袭假说提出，在绝大多数临床癌症中通过氟脱氧葡萄糖 - 正电子发射断层扫描观察到的葡萄糖代谢改变和葡萄糖摄取增加，对于侵袭性表型的发展至关重要。在该模型中，由于葡萄糖代谢改变导致的酸产生增加作为关键中间体，通过产生沿浓度梯度流入相邻正常组织的H(+)流发挥作用。肿瘤周围正常组织长期暴露于酸性微环境会通过以下方式产生毒性：(a) 跨膜H(+)梯度崩溃导致正常细胞死亡，引发坏死或凋亡；(b) 通过组织蛋白酶B和其他蛋白水解酶的释放导致细胞外基质降解。肿瘤细胞在致癌过程中逐渐对酸诱导的毒性产生抗性，使其能够在低pH微环境中存活和增殖。这使得它们能够不顾酸梯度而侵入受损的相邻正常组织。在此，我们描述了酸介导侵袭的理论和实验证据。使用数学模型进行的计算机模拟提供了关于肿瘤 - 宿主界面处形态以及细胞和细胞外动态的可测试预测。体内实验证实了肿瘤周围酸梯度的存在以及暴露于酸性微环境的正常组织中的细胞毒性和细胞外基质降解。酸介导的肿瘤侵袭模型提供了一种将葡萄糖代谢改变与肿瘤细胞形成侵袭性癌症的能力联系起来的简单机制。
